Indane compounds



United States Patent Office 3,097,243 Patented July 9, 1963 3,097,243(TERTIARY AMINO-LOWER ALKOXY)INDANE COMPOUNDS Royal A. Cutler, SandLake, N.Y., assignor to Sterling Drug Inc., New York, N.Y., acorporation of Delaware No Drawing. Filed July 16, 1959, Ser. No.827,439 2 Claims. (*Cl. 260--570.9)

This invention relates to basic ethers of ar-indanols and salts of saidothers, to intermediates for the same, and to preparation thereof.

More particularly, my new bases and their salts are ar- (tertiaryamino-lower alkoxy)indane compounds having the structural formula KO-lower alkyleneZ- Formula I wherein X X and X, which can be the same ordifferent, are members of the group consisting of hydrogen, lower alkyl,chlorine, bromine, and fluorine, Z represents a member of the groupconsisting of -N=B and where N=B contains 212 carbon atoms and is amember of the class consisting of di-( lower alkyD-amino, l-piperidyl,lower alkylated-l-piperidyl, 4-morph0linyl, 4-thiomorpholinyl,l-pyrrolidyl, lower alkylated-l-pyrrolidyl, l-hexamethyleniminyl, andl-heptamethyleniminyl, Y is a member of the group consisting ofhydrogen, alkyl, lower alkenyl, and lower (monocarbocyclic aryl)methyl,and An is an anion.

As will be appreciated, the new ar-tertiary aminolower alkoxy)indanes ofmy invention are the 4-(tertiary amino-lower alkoxy)indanes having thestructural formula O-lower alkyiene-Z Formula II and the S-(tertiaryamino-lower alkoxy)indanes having the structural formula Formula IIIdivalent saturated hydrocarbon bridge which joins the oxygen andnitrogen atoms of the compounds and intervenes two to five carbon atomsbetween the oxygen and nitrogen atoms, and contains a total of two tosix carbon atoms. The lower alkylene thus includes such radicals as -CHCH -CH(CH )CH=, CH CH CH and the like.

The radicals X X and X in Formulas I, II, and III above represent thesame or different members of the group consisting of: hydrogen; loweralkyl, that is, alkyl having 1-4 carbon atoms, for example, methyl,ethyl, npropyl, isopropyl, n-butyl, and the like; and chlorine, bromine,and fluorine.

The radical -N=B in Formulas I, II, and III above is a basic,aliphatic-type disubstituted amino radical which contains 2l2 carbonatoms and includes: (Ii-(lower alkyUamino wherein the two lower alkylradicals are the same or different, and each lower alkyl contains fromone to six carbon atoms, for example dirnethylamino, diethylamino,ethylmethylamino, isopropylrnethylamino, diisopropylamino,ethyl-n-propylamino, di-(n-butyl)amino, di-(n-hexyl)amino, and the like;l-piperidyl; lower alkylated-l-piperidyl, that is l-piperidyl bearingmethyl and/or ethyl substituted on the carbon atoms thereof, for example2-methyl-l-piperidyl, 3-ethyl-l-piperidyl, 4- methyl-l-piperidyl,2-methyl-4-ethyl-l-piperidyl, 2,6-dimethyl-I-piperidyl, and the like;4-morpholinyl; 4-thiomorpholinyl; l-pyrrolidyl; loweralkylated-l-pyrrolidyl, that is l-pyrrolidyl bearing methyl and/or ethylsubstitut-ed on the carbon atoms thereof, for exampleZ-methyll-pyrrolidyl, 3-ethyl-l-pyrrolidyl,3-methyl-4-ethyl-l-pyrrolidyl, 2,S-dimethyl-l-pyrrolidyl, and the like;l-hexamethyleniminyl; and l-heptamethyleniminyl.

It will be understood of course that when the radical Z in Formula Iabove is -N=B, the resulting structural formula O-lower alkylene-N=BFormula V represents the acid-addition salts of my new bases when Y ishydrogen, and the quaternary ammonium salts of my new bases when Y isother than hydrogen, that is, alkyl, lower alkenyl, or lower(monocarbocyclic aryl)- methyl. As is readily apparent, theacid-addition salts and the quaternary ammonium compounds possess thesame structural nucleus as the bases, and the structure of 3 the basesthus constitutes the common characteristic feature of the three forms ofthe 4- and 5-(tertiary aminolower a1koxy)indane compounds of myinvention.

The acid-addition salts (Formula V: Y=hydrogen) are convenientlyprepared by interacting the free base with an approximately equivalentamount of the appropriate acid, H--An, in a suitable inert organicsolvent medium. The resulting acid-addition salt is isolated in theusual manner, that is by cooling the solution to cause separation of thesalt, after concentrating the solution if necessary, or the solvent isevaporated to leave the salt as a residue.

The acids used in forming the acid-addition salts (Formula V:Y:hydrogen) can be either organic or inorganic, weak or strong; and allof the resulting salts are useful. The choice of acid to be used will ofcourse be dependent on the specific need involved. For example, someacid-addition salts are adapted to purposes of characterization,identification, or purification, and each is useful to regenerate thecorresponding base if the acidaddition salt itself is found unsuited forsome purposes. Pharmacodynamically acceptable acid-addition salts are ofcourse prepared when a pharmaceutical use is contemplated; among suchsalts are those derived from hydrochloric acid, hydrobromic acid,hydriodic acid, phosphoric acid, sulfuric acid, sulfonic acid,ethanesulfonic acid, tartaric acid, citric acid, succinic acid, aceticacid, benzoic acid, quinic acid, oleic acid, tannic acid, and the like.If the particular acid-addition salt (Formula V: Y:I-I) at hand does nothave the appropriate toxicity or solubility characteristics for thedesired purpose, the base (Formula I) is regenerated in the usual mannerby treating the acid-addition salt with a strong alkali, and the basecan then be converted to a suitable acid-addition salt.

The hydrochlorides are the preferred acid-addition salts for most uses.

In the quaternary ammonium salts (Formula V: Y=other than H), alkylpreferably contains about 1-18 carbon atoms, lower alkenyl preferablycontains about 1-6 carbon atoms, and lower (monocarbocylic aryl)methylpreferably contains about 7-12 carbon atoms. When An represents theanion of a strong inorganic acid or of a strong organic sulfonic acid,the quaternary ammonium salts are obtained by the addition of an alkyl,lower alkenyl or lower (monocarbocyclic aryl)methyl ester of the strongacid to the free base form (Formula IV) of my new compounds. Thequaternizing esters, which form a well-known class in the quaternaryammonium art, include such compounds as methyl chloride, methyl bromide,methyl iodide, ethyl bromide, propyl chloride, n-hexyl chloride,isooctyl iodide, stearyl bromide, lauryl chloride, allyl chloride, allylbromide, methyl sulfate, methyl benzenesulfonate, methylptoluenesulfonate, benzyl chloride, benzyl bromide, and substitutedbenzyl halides, such as p-chlorobenzyl chloride, p-nitrobenzyl chloride,p-methoxybenzyl chloride, p-isopropylbenzyl chloride, o-chlorobenzylchloride, and the like. The quaternization reaction is carried out inconventional fashion by interacting the free base and the quaternizingester in an inert solvent. Heating may be used to facilitate thereaction, but the quaternary salt formation usually takes place readilywhen the reactants are mixed at room temperature. The quaternaryammonium salt separates directly or can be obtained by suitableconcentration of the reaction solution or removal of the solvent. WhenAn in a desired quaternary ammonium salt is the anion of a weak acid,and it is not ordinarily possible to employ direct quatemization,conversion of one quaternary ammonium salt to another in which the anionis dilferent is carried out in the usual general fashion. Thus, aquaternary ammonium salt containing an anion which forms awater-insoluble silver salt is obtained by direct quaternization andthen reacted with silver hydroxide (aqueous suspension of silver oxide)in aqueous medium to form the corresponding quaternary ammoniumbydroxide, the original anion being removed as a precipitate. Forinstance, a quaternary ammonium chloride (Formula V: Yzother than H;An:Cl) can be used for this purpose of conversion, in which case theprecipitate obtained is silver chloride. The quaternary ammoniumhydroxide solution produced in this fashion is then neutralized with theappropriate acid, either weak or strong, to produce the desired newquaternary ammonium salt in which the anion is different from that ofthe original salt.

The compounds of my invention in free base form (Formula IV) areproduced by interacting a suitable metal salt, such as an alkali metalsalt, or an air-indanol having the structural formula Formula V1 with atertiary amino-lower alkyl halide, halogen-lower alkylene N:B, wherein XX and X lower alkylene, and -N:B have the same significance set forthhereinabove. The formation of the alkali metal salt of the indanol isconveniently carried out by interacting the indanol (Formula VI) and analkali metal base, for instance an alkali metal or an alkali metalhydride, lower alkoxide, or hydroxide, such as sodium, potassium,lithium, sodium hydride, potassium hydride, lithium hydride, sodiumethoxide, sodium isopropoxide, sodium hydroxide, potassium hydroxide,and the like. The resulting salt, without isolation if desired, is thentreated with an approximately equivalent amount of the tertiaryamino-lower alkyl halide, thereby producing the 4- or S-(tertiaryamino-lower alkoxy)indane (Formula IV). This latter reaction is carriedout at room temperature or, if preferred, at higher temperatures such as-150" C., or conveniently at the reflux temperature of the reactionmixture when a solvent is used. Advantageously, these reactions arecarried out in the presence of a suitable inert liquid solvent, such asa lower alkanol, for eX- ample methyl alcohol, isopropyl alcohol, andethyl alcohol, or N,N-dimethylformamide.

The structures of the compounds of my invention are established by themode of their preparation and by chemical analysis establishing thepercentage composition of carbon, hydrogen, and nitrogen, the percentageoxygen content being obtained by difference. The presence of a singlebasic nitrogen atom is confirmed by analysis of the bases and the saltsobtained therefrom.

The new compounds (Formula I) of my invention have been found to havebiocidal and biostatic activities, and they are useful for combattingdeleterious bacteria and fungi present on surface areas of widelyvarying types, including surfaces which are either living or ofinanimate nature, such as mucous membrane, skin, hair, fur, cloth,walls, floors, glassware, and the like. In such use, my new compoundsare applied topically in any appropriate fashion, as by spraying,swabbing, immersing, or similar treatment of the surface on which theantibacterial or antifungal effect is desired. As will be appreciated,the particular mode of application in any given instance is chosen so asbest to meet the requirements involved. For certain purposes, forexample in disinfection of nonliving objects of wood or metal, the 4- orS-(tertiary aminoalkoxyfindane, or preferably an acid-addition orquaternary ammonium salt thereof, can be applied per so if desired.Generally speaking, however, it has been found preferable to apply thecompounds, in a concentration of at least 0.1 percent by weight, inadmixture with a suitable carrier; the carrier can be biologicallyinert, or on the other hand can have biological activity, for exampleantibacterial or antifungal activity, or can contain other biologicallyactive ingredients,

For application of compositions containing the compounds (Formula I) toliving tissue, it is of course de sirable and usually necessary that thecarrier be innocuous and pharmaceutically acceptable; that is to say,the carrier should be substantially non-irritating, free ofobjectionable odor, and of low toxicity. Pharmaceutically acceptablecarriers are of course well known in the pharmaceutical art and include,for example, powders such as talc, precpitated calcium carbonate,starches, and gums; ointments such as petrolatum, hydrogenated oils,soft fats and waxes, intermediately polymerized ethylene oxide andmonoor di-glycerides of fatty acids; creams such as cetyl alcohol,stearic acid, oleic acid, and lanolin; jellies such as starch,tragacanth, agar-agar, and gelatin; liquid diluents, as for examplewater, liquid petrolatum, ethyl alcohol, vegetable oils, polyethyleneglycol, acetone, glycerol, and syrups; and the like.

When applied by the above mentioned methods, the new compounds (FormulaI) have useful bactericidal and bacteriostatic activity against a numberof bacterial species. The following species are illustrative:Staphylococcus aureus, 209; Eberthella typhi, Hopkins; Clostridiumwelchii, M; and M ycobacterium tuberculosis, H37Rv; against thesespecies the minimum bacteriostatic and bactericidal concentration byweight of the compounds of the examples described below were found tofall generally in the range from about 1:1000 to about 1:l20,000 asmeasured by conventional serial dilution techniques. The following fungiare illustrative of the species against which my compounds (Formula I)have useful 'fungistatic and fungicidal activity: Trichopkytonmenmgrophytes, Aspergilllrs niger, and Monilia albicans; against thesespecies the minimum fungistatic and fungicidal concentrations by weightof my compounds of the following examples were found to fall gen-erallyin the range from about 1:1000 to about l:l35,000 as measured byconventional serial dilution techniques.

The indanols (Formula VI) used as starting materials for the preparationof my new compounds (Formula I) are old as a general class, and arereadily prepared by known general procedures. For instance, a method ofgeneral applicability which can be employed involves interacting aphenol, X X X C H OH, in which the 3-position and at least one of the 2-and 4-positions of the phenol are unsubstituted, withbeta-chloropropionyl chloride, thereby forming the beta-chloropropionateester of the phenol. On heating this ester with aluminum chloride at95-120 C. it rearranges to form the ortho-(beta chloropropionyl) phenol,and/or the para-(beta-chloropropionyl) phenol, depending on whether anortho or the para-position, or both, of the starting ester isunsubstituted. This rearranged product is cyclized by heating withaluminum chloride at 165170 C. to produce a 4hydroxyl-indanone from anortho-(beta-propionyl)phenol or a S-hydroxy-l-indanone from apara-(beta-propionyl)- phenol. Reduction of these indanones with zincand hydrochloric acid yields an indanol (Formula VI) with the hydroxylat the 4-position or the 5-position, respectively. The reactionconditions in the cyclization step can be readily adjusted to favor theproduction of either the 4- or the S-indanol compound, if both arepossible, as desired. As will be obvious, when X is other than hydrogenand occupies the para position in the starting phenol, only a 4-indanolderivative is possible and is produced. This procedure is illustratedbelow in Example D.

Monoand dichloro-4- and S-indanols, which are also preparable by theabove general procedure, can be obtained by chlorination of 4- and5-indanols, as shown in Canadian Patent 557,116, granted May 6, 1958,and British Patent 770,593, published March 20, 1957.

My invention is illustrated by the following examples without, however,being limited thereto.

6 EXAMPLE 1 5 -(3-Diethylaminopropoxy)Indane A. A solution of sodiumisopropoxide was prepared by adding 4.8 g. of sodium hydride in smallportions to 200 m1. of anhydrous isopropyl alcohol. To this solution ina 500 ml. round-bottom flask fitted with a stirrer, dropping funnel, andreflux condenser with drying tube attached there was added 26.8 g. ofS-indanol, and the resulting solution was heated to reflux temperature.The stirrer was then started, and 30 g. of 3-diethylarninopropylchloride was added dropwise to the refluxing solution over a period ofone hour. After this addition was completed, refluxing was continued forfifteen minutes more, and then the isopropyl alcohol was removed fromthe reaction mixture by distillation under reduced pressure. The residuein the distillation flask was diluted with 500 ml. of water and the oilylayer which formed was dissolved in about 500 ml. of ethyl ether. Theethereal layer, which contained the desired product,5-(3-diethylarninopropoxy)indane, was separated from the aqueous layer.The ethereal layer was then extracted with a solution of 18 ml. ofconcentrated hydrochloric acid in 300 ml. of water and the acidicaqueous extract was separated and mixed with 50 ml. of 35 percentaqueous sodium hydroxide solution, thus causing the separation of anoil. This oil was dissolved in ethyl ether, the solution was dried overanhydrous calcium sulfate, and then the ethyl ether Was removed bydistillation under reduced pressure. There was obtained as a residue 43g. of a pale yellow oil, which was then distilled under reducedpressure. The fraction distilling at l24l25 C. (0.2 mm.) was a colorlessoil, n =l.5l03, which weighed 36 g.; it consisted of5-(3-diethylaminopropoxy)- indane, having the structural formula OH:01H, o-cmomcmrv our5 Analysis.-Calcd. for C H NO: N, 5.66. N, 5.72.

B. In the foregoing procedure, equivalent amounts of, metallic sodium,potassium hydride and lithium hydride, respectively, can be substitutedfor the sodium hydride with similar satisfactory results.

C. The hydrochloride of the above base was prepared by dissolving 16 g.of 5-(3-diethylaminopropoxy)indane in 50 ml. of isopropyl alcohol andadding 14 ml. of 5.6 N alcoholic hydrogen chloride solution. When thesolution was chilled, the desired hydrochloride separated as a whiteflufly solid. This solid was collected on a filter and was washed firstwith cold isopropyl alcohol and then with ethyl ether, and the productwas then dried for two hours at 70 C. There was thus obtained 12.5 g. of5-(3-diethylaminopropoxy)indane hydrochloride as a white crystallinesolid which melted at 106-109 C. Analysis.Calcd. for C ,;H NOl-ICl: C,67.70; H, 9.23; Cl, 12.49. Found: C, 67.80; H, 8.75; CI, 12.49.

D. The methiodide of the base was prepared in the folling manner. 10 g.of 5-(3 diethylaminopropoxy)indanc and 8.5 g. of methyl iodide weredissolved at room temperature (about 26 C.) in 50 ml. of acetonitrile ina ml. round-bottom flask. Immediately after the reactants were mixed thetemperature of the reaction mixture rose rapidly to about 49 C. Thereaction mixture was allowed to stand overnight at room temperature, andcarbon tetrachloride was then added to the solution until a slightcloudiness persisted. The mixture was then chilled and after severalhours the white platelets which had separated from solution werecollected on a filter and washed with carbon tetrachloride. On standingin air, the product became yellow. It was purified by dis- Found:

solving the crystals in hot benzene, decanting the hot benzene solutionfrom a small amount of undissolved oil, and then cooling the benzenesolution. The white crystals which separated from solution werecollected on a filter. There was thus obtained 3.1 g. of5-(3-diethylaminopropoxyfindane methiodide having the structural formulaon, I

This product melted at 105-107 C. AnaIysis.-Calcd. for C H INO: C,52.46; H, 7.25; I, 32.61. Found: C, 52.32; H, 6.82; I, 32.5.

E. Silver hydroxide is mixed with 5-(3-diethylaminopropoxy)-indanemethiodide in aqueous solution, and the silver iodide which precipitatesfrom the reaction mixture is collected on a filter. By evaporating thewater from the filtrate, there is obtained N,N-diethyl-N-methyl-N-[3-(indan-S-yloxypropyl) -arnmonium hydroxide, having the structuralformula This product is a strong base which reacts readily with acids toyield the corresponding quaternary ammonium salts. For instance itreacts with lactic acid to yield 5- (3-diethylaminopropoxy)indane methyllactate having the structural formula CH: (EH5 4 -CHICH2CHz-N C\2 CgH 0co ouon on.

F. The 2-chlorobenzyl chloride salt of the base was prepared as follows.A mixture of g. of 5 -(3-diethylaminopropoxyfindane and 6.5 g. of2-chlorobenzyl chloride was placed in a 50 ml. one-neck flask and warmedon a steam bath for one and one-half hours. After the resulting oilyreaction product had been allowed to stand at room temperature for oneweek it crystallized spontaneously. The solid thus obtained wasrecrystallized twice from benzene and then dried at 70 C. There was thusobtained 7.2 g. of S-(S-diethylaminopropoxy)indane 2-ohlorobenzylchloride, having the structural formula as a white crystalline solidwhich melted at 139-142 C. Analysis.-Calcd. for C H Cl NO: Cl, 17.34; N,3.43. Found: Cl, 17.36; N, 3.33.

EXAMPLE 2 4-(S-Dimethylaminopropoxy)Indane Proceeding in accordance withthe mani ulative procedure of part A of Example 1, but substituting 26.8g.

of 4-indanol for the 5 indanol, and substituting 33.2 g. of3-dimcthylaminopropyl bromide for the 3-diethylaminopropyl chloride, theproduct obtained is 4-(3-dimethylaminopropoxy)indane, having thestructural formula This base reacts with one equivalent of hydrogenchloride to yield 4-(3-dimethylaminopropoxy)indane hydrochloride; andtreatment of the base with one equivalent of methyl iodide yields4-(3-dimethylaminopropoxy)indane methiodide, having the structuralformula CH3 CH3 EXAMPLE 3 4-(3-Diethylamin0pr0p0xy )Indane A. Proceedingin the manner described above in part A of Example 1, but using 26.8 g.of 4-indanol instead of S-indano], there was obtained as the reactionproduct a pale yellow oil which was distilled under reduced pressure.The fraction distilling at ll21l5 C. (0.15 mm.) was a colorless oilwhich weighed 32.9 g. and had n =l.5l39. This product was4-(3-diethylaminopropoxy)indane, having the structural formulaOCH2CHzCHr-N K C1115 Analysis.Calcd. for C H NOz C, 77.68; H, 10.19.Found: C, 76.57; H, 9.96.

B. The hydrochloride of the above base was prepared as follows. To asolution of 5 g. of 4-(3-diethylaminopropoxy)-indane in 1 00 ml. ofanhydrous ethyl other there was added 4 ml. of 6 N alcoholic hydrogenchloride solution. When the resulting solution was allowed to stand atroom temperature, a white crystalline solid separated from solution.This product was collected on a filter and then was recrystallized fromisopropyl alcohol. There was thus obtained 4.1 g. of4-(3-diethylaminopropoxyfindane hydrochloride as white crystals whichmelted at l44146 C. Analysis.Calcd. for C H NO.HCl: C, 67.71; H, 9.24;Cl, 12.49. Found: C, 67.40; H, 9.21;Cl, 12.24.

C. 4-(3-diethylarninopropoxy)indane reacts with one equivalent of benzylbromide to yield 4-(3-diet-hylarninopropoxy)indane benzyl bromide,having the structural formula 9 10 EXAMPLE 4 EXAMPLE 64-(2-Dimethylaminoethoxy)Indcme 4-(Z-Diethylaminoethoxy)IndaneProceeding as described above in part A of Example 1, Employing theprocedure described in part A of Exambut substituting 26.8 g. of4-indanol for the S-indanol ple l, but substituting 26.8 g. of 4-indano1for the 5-inand substituting 30.5 g. of 2-dimethylaminoethyl bromidedanol and substituting 27.2 g. of 2-d1ethy1am1noethyl for the3-diethylarninopropyl chloride, the product obchloride for the 3-diethyp py chlofidei the P Q tained is 4-(2-dirnethylaminoethoxy)indane,having the uct obtamed 1S 4-(2-diethylamlnoethoxy)indane, havingstructural formula the structural formula CH; CIHE OCH2CH:-N\ CH: CH;CH: C2135 CH: CH:

CH1 CH2 This base reacts with one equivalent of hydrogen chlorine Thisase reads with ne equivalent of hydrogen chloto form4-(Z-dlmethylaminoethoxy)indane hydrochloride. ride to form4-(Z-chethylammoethoxy)rndane hydro- The base reacts with one equivalentof methyl iodide to ChlOflde- The base reacts Wlth 0116 eqlllvalfim ofmethyl yield 4-(2-dimethylaminoethoxy)indane methiodide, haviodide U0form 4-(z-dlethylammoethoxy)illdane methioing h structural fg la dide,which is chemically identical with the compound designated by thealternative nomenclature 4-(2-ethyl- (3113 methylaminoethoxyfindaneethiodide in Example 5. O' CH2CHI N EXAMPLE 7 i ori 44-[2-(N-Isopropyl-N-Methylamino)Ethoxfllndane C 2 Proceeding in themanner described above in part A of Example 1, but substituting 26.8 g.of 4-indanol for CH: the S-indanol and substituting 27.2 g. ofZ-(N-isopropyl- N-methylamino)ethyl chloride for the S-diethylamino-EXAMPLE 5 propyl chloride, there is obtained as the reaction product 4[2 (N Ethyl N Melhyiamino)Ethoxyundane4-[2-(N-isopropyl-N-methylamino)ethoxy]indane, having th struct 1 form 1By substituting 26.8 g. of 4-indanol for the S-indanol 5 e um u a and bysubstituting 24.2 g. Z-(N-ethyl-N-methylamino)-ethyl chloride for theB-diethylaminopropyl chlo- 0H; ride in the procedure of part A ofExample 1, there is obtained as the reaction product4-[2-(N-ethyl-N-methylamino)ethoxy]indane, having the structural formulaCH3 CH2 O-CH2CH:N/ CH/ on 2 i g This base reacts with one equivalent ofmethyl iodide to C 2 yield 4 [2 N isopropyl N methylamino)ethoxylindanemethiodide, having the structural formula CH; CH: This base reacts withone equivalent of hydrogen bromide 5 to yield4-[2-(N-ethyl-N-rnethylarnino)ethoxylindane hy- 0 OCHzCHz-N drobromide.The base reacts with one equivalent of 0H, (HUGH) ethyl iodide to yield4-[2-(N-ethyl-N-methylarnino)eth oxy]indane ethiodide, having thestructural formula. CH2 x CgH CH;

o-oniom-iir 1 and reacts with one equivalent of benzyl bromide to yieldOH 4- 2-( N-isopropyl-N-methylamino )ethoxy] indane benzyl bromide,having the structural formula CHa CHQCQHQ and melting at approximately100104 C. and reacts with one equivalent of allyl chloride to yield4-[2-(N- ethyl-N-methylamino)ethoxy]indane allyl chloride, hav- 2 mg thestructural formula 5 Br Caronon, C

CH3 CHz OCH:CH2- CH, H EXAMPLE 8 2 6 I 5-[2-(N-Isopropyl-N-Merhyl'amno)EthoxyJIIzdane Proceeding as in part A of Example 1, but using 27.2g. of 2-(N-isopropyl-N-methylamino)ethyl chloride in place of the3-diethylaminopropyl chloride, the product 1 1 obtained is-[2-(N-isopropyl-N-methylamino)ethoxy]- indane, having the structuralformula CHa CH3 O-CH2CH2N CH1 This base reacts with one equivalent ofmethyl iodide to yield 5- 2- (N-isopropyl-N-methylamino ethoxy indanemethiodide, having the structural formula CH. g -0c1non,-s 1 2 I 011mmEXAMPLE 9 S-(Z-Diethylaminoethoxy)Indane Analysis.-Calcd. for C H NO: N,6.00. Found:

B. The hydrochloride of the above base Was prepared by dissolving 1g. of5-(2diethylaminoethoxy)indane prepared in accordance with the method ofpart A above in 70 ml. of isopropyl alcohol and bubbling gaseoushydrogen chloride into the solution until the solution was slightlyacidic. The reaction mixture was diluted with 800 ml. of ethyl ether andchilled at 6 C. overnight. The crystalline solid which had separatedfrom the solution was then collected on a filter. This product, whichweighed 29.6 g. and melted at 137-139 C., was 5-(2'diethylaminoethoxy)indane hydrochloride. Analysis. Calcd. for C H NOHCl:C, 66.76; H, 8.96; Cl, 13.14. Found: C, 66.65; H, 8.93; Cl, 13.16.

C. The above base reacts with one equivalent of methallyl bromide toyield 5-(Z-diethylaminoethoxy)indane methallyl bromide, having thestructural formula and with one equivalent of stearyl chloride to yield5-(2- diethylaminoethoxy)indane stearyl chloride, having the structuralformula oestrous cm 4 OCH;OH -N C I C2115 EXAMPLE 1'05-(3-Dimethylaminopropoxy)Indane Proceeding as in part A of Example 1,except that 12 24.2 g. of 3-dimethylaminopropyl chloride is substitutedfor the 3-diethylaminopropyl chloride, the product obtained is5-(3-dimethylaminopropoxy)indane having the structural formula CH2 /CH3-0C HzCHzCHzN on,

This base reacts with one equivalent of methyl iodide to yield 5 (3dimethylaminopropoxy)indane methiodide, having the structural formulaand reacts with one equivalent of p-methylbenzyl chloride to yield5-(S-dimethylaminopropoxy)indane p-methylbenzyl chloride, having thestructural formula on, CH3 o-cmomoupzv a... 1 CH, 6112/ (:1

EXAMPLE 11 5,7-Dimcthyl-4-(3-Diethylamin0pr0poxy)Indane A. To anice-cooled solution of 50 g. of 4-indanol in 50 m1. of isopropyl alcoholthere was added an ice-cooled solution of 60 g. of dimethylamine in 200ml. of water. The resulting solution was then further cooled to about 0C. and 93 ml. of formalin was added dropwise, the temperature of thereaction mixture not being allowed to rise above 7 C. After thisaddition was completed, ml. of isopropyl alcohol was added, and themixture was refluxed for three hours. The solvent and excess volatilereactants were removed by distillation under reduced pressure(water-pump), and the residual oil was distilled under reduced pressure.The fraction distilling at 137-l4l C. (0.3 mm.) was a colorless oil, 111.5340, which weighed 56.5 g.; this product was 5,7-bis(dirnethylaminomethyl)-4-indanol, having the structural formula OH011. l

Analysis.Calcd. for C H N O: N, 11.28. Found: N, 11.25.

B. 56.5 g. of 5,7-bis(dimethylaminomethyl)-4-indanol was catalyticallyreduced with hydrogen in the presence of 7 g. of copper chromitecatalyst in a bomb at a pressure of 2900 pounds per square inch andl15l20 C. The reduction product was isolated as follows. The bombcontents were cooled, and then mixed with 400 ml. of ethyl ether, andthe mixture was filtered to remove the catalyst. The ethereal filtratewas washed twice with 400 ml. portions of 1.25 N aqueous hydrochloricacid and then twice with water. The ether layer was dried over anhydrouscalcium sulfate, the drying agent was then removed, and the etherealsolution was distilled to remove the ether. The residual oil, whichweighed 30.1 g., solidified on cooling; this solid, which was white.

13 melted at 7076 C. After crystallizations from petroleum ether, thisproduct weighed 19.8 g. and melted at 102-109 C.; it consisted of5,7-dimethyl--indanol, having the structural formula C. 1.5 g. of sodiumhydride was dissolved in 55 ml. of isopropyl alcohol and the resultingsolution was mixed with 8.5 g. of 5,7-dimethyl-4-i11danol and heated. Tothis hot mixture there was slowly added 8.4 g. B-diethylaminopropylchloride. The resulting product was a red oil. Attempted distillation ofthis oil at 145 C. (0.2 mm.) gave indications of decomposition, so thedistillation was discontinued. The oil was then dissolved in ethyl etherand the solution was extracted with 17 ml. of 3 N hydrochloric acid. Theacidic aqueous extract was separated and was made strongly alkaline byaddition of 35 percent aqueous sodium hydroxide solution. The desired5,7-dimethyl 4 (3-diethylarninopropoxy)indane having the structuralformula C5115 (IJCHgCH CHglN CH n separated from solution as an oil.

D. The base obtained in the above described manner was converted to thehydrochloride salt as follows. The oil was dissolved in ethyl ether andthe ethereal solution Was dried over anhydrous colcium sulfate and thenfiltered with decolorizing charcoal. To the filtrate, which was almostcolorless, there was added sufiicient alcoholic hydrogen chloridesolution to make the filtrate slightly acidic. The slightly yellow solidwhich precipitated from solution was collected on a filter and dried ina desiccator. The dry solid was slurried in anhydrous ethyl ether,collected on a filter, and then recrystallized twice from toluene. Therewas thus obtained 2 g. of 5,7-dimethyl 4 (3-diethylaminopropoxy)indanehydrochloride as a white crystalline solid which melted at 124- 127 C.Analysis.-Ca lcd. for C H NQHCI: Cl, 11.37; N, 4.49. Found: Cl, 11.43;N, 4.42. The base also interacts with acetic acid, boric acid. citricacid, p-toluenesulfonic acid, nitric acid, sulfuric acid, and phosphoricacid to form the corresponding acetate, borate, citrate,p-toluenesulfonate, nitrate, sulfate, and phosphate acid addition saltsof 5,7-dimethyl-4-(3-diethylaminopropoxy indane.

E. Interaction of 5,7-dimethyl 4-(B-diethylaminopropoxy)indane with oneequivalent of n-hexyl bromide yields 5,7-dimethyl 4 (3diethylaminopropoxy)inclane n-hexyl iodide, having the structuralformula EXAMPLE 12 6-]llethyI-4-(3 -Dieth ylaminopropoxy I ndaneProceeding as in part C of Example 11, except that 14 7.7 g. of6-rnethyl4-indanol is substituted for the 5,7- dimethyl-4-indanol, thereis obtained 6-rnethyl-4-(3-diethylaminopropoxy)indane, having thestructural formula CH2 czHi This base reacts with hydrogen bromide toyield 6-methyl- 4-(3-diethylaminopropoxy)indane hydrobromide, and reactswith one equivalent of benzyl chloride to yield 6-methyl-4-(3-diethylaminopropoxy)indane benzyl bromide, having thestructural formula CaHs CI)-CH2CHzC HgN CzHs CH2 I Br EXAMPLE 134,6-Dimcthyl-5-(Z-Diethylaminoetlzoxy lndaize A. Proceeding in themanner described in part A of Example 11, and using the followingreactants: g. of S-indanol; a solution of g. of dimethylarnine in 400ml. of water; 186 ml. of formalin; and 100 ml. of isopropyl alcohol,followed by a 300 ml. portion of this compound after the formalinaddition step. the reaction product obtained was an oil, which wasdistilled under reduced pressure. The fraction distilling at l37 C. (0.2mm.) was a colorless oil, n =1.5356, which weighed 148.6 g.; thisproduct was 4,6-bis(dimethylaminomethyl)-5-indanol, having thestructural formula Analysis.Calcd. for C H N O: N, 11.28. Found: N,11.20. This base in isopropyl alcohol reacted with hydrogen chloride inethyl alcohol to yield the base dihydrochloride, M.P. 2l5218 C.Analysis.Cal-cd. for C15H24N20-2HC1I C, H, Cl, Found: C, 55.95; H, 8.06;Cl, 21.94.

B. 58 g. of 4,6bis(dimethylaminomethyl)-5-indanol was catalyticallyreduced for one hour with hydrogen in the presence of 6 g. of copperchromite catalyst, in a bomb at a pressure of 3600 pounds per squareinch and at 131-135 C. The bomb contents were then cooled and dilutedwith 400 ml. of ethyl ether, and the resulting solution was filtered toremove the hydrogenation catalyst. The purple ethereal filtrate waswashed twice with 400 ml. portions of 1.25 N aqueous hydrochloric acid,which removed the purple color, and then was washed twice with water.The ether layer was dried over anhydrous calcium sulfate, the dryingagent was removed by filtration, and the filtrate was distilled toremove the ether. The residual pale yellow oil, which weighed 35.4 g.,solidified on cooling. After two recrystallization-ls from petroleumether, this product melted at 7980 C.; it was 4,6-dimethyl-5-indanol,having the structural formula CH3 CH3 Analysis.--Calcd. for C H O: C,81.45; H, 8.70; O, 9.86. Found: C, 81.02; H, 9.00; O, 9.60. Thiscompound was found to have antibacterial and antifungal properties. Forinstance, the minimum bacteriostatic concentrations againstStaphylococcus aureus 209 and Eberthella typhi Hopkins were 1:100,000and 1:1000, respectively; and the minimum bactericidal concentrationagainst the same species was 1:1000 in each case, as measured byconventional serial dilution techniques. The minimum fungistaticconcentration against Trichophyton mcntagrophytes, Aspergillus niger,and Monilia albicans was l:10,000 in each instance; and the minimumfungicidal concentrations were 1:10,000 against the first species andless than 1: 0.000 against the latter two species, using conventionalserial dilution techniques.

EXAMPLE 14 4,6-Dimetl1y[-5-(3-Diethylamin0pr0p0xy)Indane A. To asolution prepared by dissolving 2 g. of sodium hydride in 75 ml. ofisopropyl alcohol there was added 11.5 g. of 4,6-dimethyl-5-indanol. Theresulting mixture was heated, and 11 g. of S-diethylaminopropyl chloridewas gradually added thereto. The reaction product was isolated as a paleyellow oil which was then distilled under reduced pressure. The fractiondistilling at 136- 137 C. was a colorless oil, n :1.5096, which weighed11.5 g.', it consisted of 4,6-dimethyl-5-(3-diethylaminopropoxy)indane,having the structural formula CH2 can Analysis.-Calcd. for C H NO: N,5.09. N, 5.09.

B. 13.5 g. of 4,6-dimethyl-5-(3-diethylaminopropoxy)- indane wasdissolved in 90 ml. of anhydrous ethyl ether and then 10 ml. of 6 Nalcoholic hydrogen chloride solution was added. After chilling thereaction mixture in a refrigerator for three days, the dense whitecrystalline solid which had separated from solution was collected on afilter. This product, which was4,6-dimethyl-5-(3-diethylaminopropoxy)indane hydrochloride, melted at128- 131 C. AnaIysis.-Calcd. for C H NOHCI: C, 69.31; H, 9.70; C1,11.37. Found: C, 69.32; H, 9.25; Cl, 11.50. The base reacts withhydrofluoric acid, formic acid, picric acid, succinic acid, and stearicacid to yield the corresponding hydrofluoride, formate, picrate,succinate, and stearate acid-addition salts of4,6-dimethyl-5-(3-diethylaminopropoxyfindane.

C. Treatment of 4,6-dimethyl-5-(3-diethylaminopropoxy)indane with oneequivalent of m-nitrobenzyl bromide yields4,6-dimethyl-5-(3-diethylaminopropoxy)indane m-nitrobenzyl bromide,having the structural formula Found 2 16 EXAMPLE 157-ChI0r0-4-(3-Diethyl'aminopr0poxy)Indane A. 7 g. of sodium hydride wasdissolved in 255 ml. of isopropyl alcohol, and to this solution therewas added 40 g. of 7-chlor0-4-indanol. The resulting mixture was heatedand 36 g. of 3-diethylaminopropyl chloride was added gradually. Thereaction product was isolated as an oil which was then distilled. Thefraction distilling at 168173 C. was a colorless oil, n =1.5242, whichweighed 22.4 g.; this product was7-chloro-4-(3-diethylaminopropoxy)indane, having the structural formulaAnaJysis.-Calcd. for C H ClNO: N, 4.97. Found: N, 4.97.

B. 19.4 g. of 7-chloro-4-(3 diethylaminopropoxy)indane was dissolved in65 ml. of isopropyl alcohol and to this solution there was added 12.5ml. of 6.14 N alcoholic hydrogen chloride solution. Ethyl ether wasadded to the reaction mixture to a point just short of permanentturbidity, and the mixture was allowed to stand at room temperature. Thewhite crystalline solid which separated from solution was collected on afilter. This product, which was 7-chloro-4-(3-diethylaminopropoxy)indanehydrochloride, weighed 11.2 g. and melted at -147 C. Analysis.Calcd. forC H ClNO.HCl: Cl, 22.28. Found: Cl, 22.05. The base reacts withp-nitrobenzoic acid and oleic acid to yield the correspondingp-nitrobenzoate and oleate acid-addition salts of7-chloro-4-(3-diethylaminopropoxy)indane.

C. Interaction of 7-chloro-4-(B-diethylaminopropoxy)- indane with oneequivalent of dimethyl sulfate yields7-chloro-4-(3-diethylaminopropoxy)indane methosulfate, having thestructural formula CzHs (SO CHa) D. The 7-chloro-4-indanol used as astarting material in part A above can be prepared in the followingmanner. Molten p-chlorophenol was stirred and treated dropwise with anequimolecular amount of ti-chloropropionyl chloride. After the additionwas completed, the reaction mixture was allowed to stir for three hoursat room temperature and then was heated for one hour on a steam bath.Distillation of the resulting oil gave a 90% yield of p-chlorophenylbeta-chloropropionate which boiled at 152-156 C. (11 mm.) and had 11:1.5306. Analysis.Calcd. for C H CI O Cl, 32.38. Found: Cl, 32.4.

A mixture of g. of p-chlorophenyl beta-chloropropionate with 350 g. ofanhydrous aluminum chloride was heated for five hours at 95 C. and thenfor one hour at -170 C. The reaction mixture was quenched with ice andwater. The solid which separated was collected on a filter and washedwell with water. Recrystallization of this solid from isopropyl alcohol,including treatment 17 with charcoal, yielded 45 g. of4-chloro-7-hydroXy-lindanone, having the structural formula which meltedat ll8122 C. From the mother liquors, the intermediate5,beta-dichloro-2-hydroxypropiophenone was recovered; by increasing theheating time at 165-170 in a subsequent run to two hours, the yield ofcrude indanone was raised to 70% and none of the intermediate wasrecovered.

The 4-chloro-7-hydroxy-l-indanone was purified by recrystallization fromethyl acetate to yield a product melting at 120-122 C. AnaIysis.-Caled.for CgHqClOgi C, 59.20; H, 3.86; Cl, 19.42. Found: C, 59.16; H, 3.99;Cl, 19.50. A mixture of 450 g. of 4-chloro-7-hydroxy-1- indanone in 2liters of toluene with 2 liters of acetic acid and 1500 g. of freshlyamalgamated zinc mesh) was heated with strong mechanical stirring underreflux at 90 C., and 5 liters of hydrochloric acid was added to themixture over a four hour period. After addition of the acid wascompleted, the heating and stirring were continued for four hours withoccasional additions of hydrochloric acid to a total of 7 liters. Thereaction mixture was cooled and separated from undissolved zinc. TheWater layer was separated and washed with one liter of toluene inseveral portions. The combined toluene extracts were concentrated underreduced pressure, and the residue thus obtained was crystallized from 1liter of petroleum ether after decolorizing the crystallization solutionwith charcoal. A 300 g. first crop of 7-chloro-4- indanol, M.P. 90-92 C.was collected; and by concentration and cooling of the filtrate from thefirst crop, and recrystallization of the second crop obtained thereby,another 35 g. of 7-chloro 4-indanol, M.P. 9092 C. resulted. Afterrecrystallization of the 335 g. of product from 1.5 liters of ethylenedichloride, there was obtained 310 g. of 7-chloro-4-indanol melting at9193 C. Analysis.Calcd. for C H CIO: Cl, 21.03. Found: Cl, 21.0.

EXAMPLE 16 5-Chl0r0-4- Z-Diethylmninoethmy I ndane A. 4.8 g. of sodiumhydride was dissolved in 185 ml. of isopropyl alcohol, and to thissolution there was added 29 g. of 5-chloro-4-indanol. The resultingmixture was heated and 23.8 g. of Z-diethylarninoethyl chloride wasgradually added thereto. The reaction product was isolated as an oilwhich was then distilled. The fraction distilling at 115 C. (0.2 mm.)was a colorless oil, 11 1.5235, which weighed 14.6 g.; this product wasS-chloro- 4-(2-diethylaminoethoxy)indane, having the structural formulaO-CHrCHs-N CH2\ C1 2 a Analysis.Calcd. for C H ClNO: N, 5.23. Found: N,5.17.

B. 14 g. of 5-chloro-4-(Z-diethylaminoethoxy)indane was dissolved in 50ml. of isopropyl alcohol and 9.5 ml. of 6.14 N alcoholic hydrogenchloride solution was added. The salt failed to separate on cooling, sothe isopropyl alcohol was distilled from the reaction mixture and ethylether was added. The white crystals which separated from solution werecollected on a filter. This product, which was5-chloro-4-(Z-diethylaminoethoxy)indane hydrochloride, weighed 11.5 g.and melted at 121-123 C.

AnaIysz's.-Calcd. for C H ClN0.HCl: Cl, 23.30. Found: Cl, 23.02. When asolution of the hydrochloride in water is made strongly alkaline byaddition of aqueous sodium hydroxide solution, the free base,5-chloro-4-(2- diethylaminoethoxyfindane, is regenerated as awater-insoluble oil; and separation and treatment of the base thusobtained with lactic acid yields the lactate acid-addition salt of5-ch1oro-4-(Z-diethylaminoethoxy)indane.

C. Treatment of 5-chloro-4(Z-diethylaminoethoxy)indane with oneequivalent of isobutyl chloride yields5-chloro-4-(Z-diethylarninoethoxy)indane isobutyl chloride, having thestructural formula CHHCH(CH3)| OCH2CH; CH2 H 2 I CH I EXAMPLE l75-ChIor0-4-(3-Diethylaminopropoxy)Indane A. 4.8 g. of sodium hydride wasdissolved in ml. of isopropyl alcohol, and to the resulting solutionthere was added 30 g. of 5-chloro-4-indanol. This mixture was heated and27 g. of 3-diethylaminopropyl chloride was gradually added thereto. Thereaction product was isolated as a yellow oil, which was then distilledunder reduced pressure. The fraction distilling at l26-131 C. (0.05 mm.)was a colorless oil, n =l.52l3, which weighed 11.4 g.; this product was5-chloro-4-(3-diethylaminopropoxy)indane, having the structural formula0 CH2CHZCHi CH2 CaHi CHI AnaIysis.-Calcd. for C H CINO: N, 4.97. Found:N, 4.97.

B. 16 g. of 5-chloro-4-(3-diethylaminopropoxy)indane was dissolved in 60ml. of isopropyl alcohol, and 12 ml. of 6.14 N alcoholic hydrogenchloride solution was added. Since very little solid separated from thereaction mixture, the isoporpyl alcohol was removed by distillation andthe oily residue was dissolved in ethyl ether, and the solution wasallowed to stand. The white crystalline solid which separated fromsolution was collected on a filter. This product, which weighed 14.4 g.and melted at 134- 139 C., was 5-chloro-4-(3-diethylaminopropoxy)indanehydrochloride. AnaIysis.-Calcd. for C H ClNO.HCl: Cl, 22.28. Found: Cl,22.22. The base reacts with hydrocyanic acid and with arsenic acid toyield the corresponding hydrocyanide and arsenate acid-addition salts of5-ch1oro-4- 3-diethylaminopropoxy) indane.

C. Treatment of 5-chloro-4-(3-diethylaminopropoxy)- indane with oneequivalent of m-methoxybenzyl chloride yields5-chloro-4-(3-diethylaminopropoxy)indane m-methoxybenzyl chloride,having the structural formula 19 EXAMPLE 1%7-Chl0r0-4-(Z-Diethylaminoethoxy)lndane A. 7 g. of sodium hydride wasdissolved in 255 ml. of isopropyl alcohol, and to the resulting solutionthere was added 40 g. of 7-chloro-4-indanol. This mixture was heated and32.6 g. of Z-diethylaminoethyl chloride was gradually added thereto. Thereaction product was isolated as a pale yellow oil, which was thendistilled under reduced pressure. The fraction distilling at 140-142 C.(0.2 mm.) was a colorless oil, n =1.5308, which weighed 14 g.; thisproduct was 7-chloro-4-(2-diethylaminoethoxy)indane, having thestructural formula O C likens-N CH2 CEHB Analysis.Calcd. for C H CINO:N, 5.23. Found: N, 5.06.

B. 12.5 g. of 7-chloro-4-(Z-diethylaminoethoxy)indane was dissolved in45 ml. of isopropyl alcohol, and then 8.5 ml. of 6.14 N alcoholichydrogen chloride solution was added. On cooling the reaction mixture, awhite crystalline solid separated from solution. This solid wascollected on a filter. This product, which weighed 11.1 g. and melted at165-17 1 C., was 7-chloro-4-(2-diethylaminoethoxy)indane hydrochloride.Analysis.Calcd. for C H N0.HC1: C1, 23.30. Found; Cl, 23.37. The basereacts with adipic acid and maleic acid to yield the correspondingadipate and maleate acid-addition salts of7-chloro-4-(Z-diethylaminoethoxy)indane.

C. Interaction of '7-ch1oro-4-(2-diethylaminoethoxy)- indane with oneequivalent of 2-chloro-4-methoxybenzyl chloride yields7-chloro-4-(Z-diethylaminoethoxy)indane 2-chloro-4-methoxybenzylchloride, having the structural formula CHg- -OCH3 OCHrCHr-N or can .4.

EXAMPLE 19 6-Chl0r0-5-(3-Diethylaminopr0poxy)lndane A. 7.7 g. of sodiumhydride was dissolved in 325 ml. of isopnopyl alcohol, and to thissolution there was added 50 g. of 6-chloro-5-indanol. The resultingmixture was heated, and 45 g. of 3-diethylaminopropyl chloride wasgradually added thereto. The reaction product was isolatcd as an oil,which was then distilled under reduced pressure. The fraction distillingat 166170 C. was a colorless oi], n =1.5252, which weighed 24.7 g.; thisproduct was 6-ch1oro-5-(S-diethylaminopropoxy)indane, having thestructural formula Analysis.-Calcd. for C H ClNOz N. 4.97. Found:

B. 24 g. of 6-chloro-5-(3-diethylarninopropoxy)indane was dissolved inml. of isopropyl alcohol and to this solution there was added 23.5 ml.of 4.16 N alcoholic hydrogen chloride solution. Ethyl ether was added tothe reaction mixture to a point just short of permanent turbidity andthe mixture was then allowed to stand. The white crystalline solid whichseparated from solution was collected on a filter. There was thusobtained 16.3 g. of 6- chloro-5-(3 diethylaminopropoxy)indanehydrochloride, which melted at 125127 C. Analysis.Calcd. for C HClNO-flclz C1 (ionic), 11.14. Found: C1 (ionic) 11.27. The base reactswith cholic acid to yield the cholate acid-addition salt of6-chloro-5-(3-diethylarninopr-opoxy)indane.

C. Interaction of 6-chloro-5-(3-diethylaminopropoxy) in-dane with oneequivalent of methyl p-toluenesulfonate yields6-chloro-5-(B-diethylaminopropoxy)indane methop-to-luenesulfonate,having the structural formula 5,7-Dz'cIzl0r0-4- (2-Diethylamin0ethoxyIndane A. 10.3 g. of sodium hydride was dissolved in 370 ml. ofisopropyl alcohol, and 71.1 g. of 5,7-dichloro-4-indanol was addedthereto. This mixture was heated, and 49.5 g. of Z-diethylaminoethylchloride was gradually added. The reaction product was isolated as ayellow oil, which was then distilled under reduced pressure. Thefraction distilling at 144148 C. was a colorless oil, n =1.532S, whichweighed 61 g; this product was 5,7-diehloro-4-(2-diethylaminoethoxy)indane, having the structural formulaAnalysis.-Calcd. for C H Cl NO: N, 4.64. Found: N, 4.72.

B. 36 g. of 5,7-dichloro-4-(2-diethylaminoethoxy)in dane was dissolvedin ml. of isopropyl alcohol, and to this solution there was added 21.8ml. of 6.14 N alcoholic hydrogen chloride solution and the mixture wasallowed to stand. The white crystalline solid which separated fromsolution was collected on a filter. The collected solid, which weighed18.3 g., was recrystallized from isopropyl alcohol. There was thusobtained 9.6 g. of 5,7- dichloro-4-(Z-diethylaminoethoxy)indanehydrochloride as a white crystalline solid which melted at l60169 C.Analysis.-Calcd. for C H Cl NO.HCl: C, 53.19; H, 6.55; C], 31.41. Found:C, 53.05; H, 6.23; Cl, 31.50. The base reacts with lactic acid andtrifluoroacetic acid to yield the corresponding lactate andtrifiuoroacetate acidaddition salts of5,7-dichloro-4-(Z-diethylaminoethoxy)indane.

C. Interaction of 5,7dichloro-4-(2 diethylaminoethoxy)indane with oneequivalent of di-n-butyl sulfate yields 21 5,7-dichloro-4-(2diethylaminoethoxy)indane n-butosulfate, having the structural formulaMCH;

o-omoH- H Cl 2 i CH SOt(CH2)aCH EXAMPLE 21 5,7 -Dich I0r0-4-(3-Diethylaminopropoxy)Indane A. 5.3 g. of sodium hydride was dissolvedin 210 ml. of isopropyl alcohol, and the resulting solution was mixedwith 40 g. of 5,7-dichloro-4-indanol. The mixture thus obtained washeated, and 30 g. of 3-diethylaminopropyl chloride was gradually addedthereto. The reaction product was isolated as an oil, which was thendistilled under reduced pressure. The fraction distilling at 145452 C.(0.1 mm.) was a colorless oil, n =1.5301, which weighed 17.2 g. thisproduct was 5,7-dichioro-4-(3-diethylaminopropoxy)indane, having thestructural formula Analysis..Calcd. for C H Cl NO; N, 4.43. Found: N,4.39. V B. 16 g. of 5,7-dichlor-o-4-(3-diethylaminopropoxy)in dame wasdissolved in 45 ml. of isopropyl alcohol, and to this solution there wasadded 9.4 mi. of 6.14 N alcoholic hydrogen chloride solution. Thereaction mixture was diluted with ethyl ether to a point just short ofpermanent turbidity and then allowed to stand. The white crystallinesolid which separated from solution was collected on a filter. Theproduct thus obtained, which weighed 11 1g. and melted at 117-136 0.,was 5,7-dichloro-4-(3-diethylaminopropoxy)indane hydrochloride.Analysis.-Calcd. for C H CI NQHCI: Cl (ionic), 10.05; Cl (total) 30.16.Found: Cl (ionic), 9.98; Cl (total) 29.70.

C. Interaction of S,7dichloro-4( 3 diethylaminopropoxy)indane with oneequivalent of ethyl iodide yields 5,7-dichloro-4-(3diethylaminopropoxy)indane ethiodide, having the structuralformula CH; i

D. Interaction of 5,7dichloro-4-(3 diethylaminopropoxy)=indane ethiodidein aqueous solution with silver hydroxide yields the correspondingammonium hydroxide, a strong base which reacts with benzoic acid toyield 5,7-di- 22 chloro-4-(3-diethylaminopropoxy)indane ethyl benzoate,having the structural formula EXAMPLE 22 5 ,7 -Dich!or0-4-S-Dimetlzylaminopropoxy)Indane A. A solution of sodium methoxide wasprepared by adding 2.3 g. of sodium to 70 ml. of anhydrous methylalcohol in a 500 ml. three-neck flask fitted with a thermometer,stirrer, dropping funel, and a distillation con denser. Benzene wasslowly added with stirring until the temporary localized turbidity inthe solution caused by the addition was just short of becgmipgpermanent, and then 20.3 g. 'Of 5,7-dichloro-4-indangi was added. Theresulting orange-yellow solution waeheated on a steam bath and themethyl alcohol was distilled from the reaction mixture under reducedpressure. When most of the methyl alcohol had been removed the sodiumsalt of 5.7-dichloro-4-indanol separated as a solid from the solution.Two portions of benzene were added to the residue during the latterstage of the distillation to aid in evaporation of thelast traces ofmethyl alcohol. Then ml. of benzene and 50 ml. of anhydrous dioxane wereadded to the distillation residue, the condenggpwas fitted with a dryingtube'a'nd set in upright POSitiOtlifOt' reflux, and the mixture, inwhich some of the sodiumsalt remained in undissolved, solid form, washeated to reflux temperature and stirred. Over a period of thirtyminutes, 20 g. of 3-dimethylair'rl propyl chloride was added slowlythrough the dropping iftgnnel. As this addition proceeded, the solid inthe reaction mixture disappeared and was gradually replaced by sodiumchloride which separated from the solution After addition of theS-dimethyllarninopropyl chloride complemented, refluxing was continuedfor thirty i 7 es more. After refluxing had been discontinued, about 200ml. of water wasWstir -ed with the reaction mixture The aqueous layerseparated was collected and discarded, and the benzene layer wasfiltered with decolorizing charcoal. The filtrate thus obtained wasextracted with 300 ml. of water containing 9 m1. of concentratedhydrochloric acid. The acidic aqueous extract was made Strongly alkalineby addition of 3 5 percent aqueous sodium hydroxide solution, therebycausing separation of 5,7-dichloro-4-(S-dimethylarninoas an 01'].

B. This base was converted to the hydrochloride by dissolving it inethyl ether, drying in ethereal solution over anhydrous calcium sulfate,filtering the solution, and then adding to the filtrate a solution ofhydrogen chloride in ethyl other until the filtrate became slightlyacidic. The white solid which separated from the solution was collectedon a filter. This crude product Weighed Z9 g. and melted at -172 C. Itwas recrystallized from 200 m1. of isopropyl alcohol. There was thusobtained 7.8 g. of 5.7-dichloro-4-(3-dimethylaminopropoxy)indanehydrochloride as a white crystalline solid which melted at 23 202-205"C. Analysis.Calcd. for C H Cl NOHCI: C, 51.79; H, 6.21; Cl, 32.76.Found: C, 51.48; H, 6.24; Cl, 33.00.

C. Interaction of 5,7-dichloro-4(3-dirnethylaminopropoxy)indane with oneequivalent of allyl bromide yields5,7-dichloro-4(3-dimethylaminopropoxy)indane allyl bromide, having thestructural formula CH2C1I3GH z-N CH: I

EXAMPLE Z3 5 ,7-Dich lore-4 [2-(1 -Piperidyl) Ethoxy] I ndane A. In a500 ml. three-neck flask with a thermometer insert and fitted with athermometer, stirrer, dropping funnel, and drying tube, 40.6 g. of5,7-dichloro-4-indanol was dissolved in 250 ml. of N,N-dimethylformamidewhich had been dried over calcium hydride. The stirrer was started, theflask was cooled with an ice-bath, and 9.6 g. of a 50 percent (byweight) suspension of sodium hydride in oil was added to the flaskcontents. Hydrogen was evolved, causing foaming, and the temperature ofthe reaction mixture rose to 45 C. despite the cooling. The reactionmixture was cooled to C., after which the ice-bath was removed, and theng. of 2-(l-piperidyl) ethyl chloride was added dropwise over a period ofthirty minutes. After this addition was completed, the reaction mixturewas allowed to stand for about twenty hours, and then was diluted withapproximately one liter of water. The resulting solution was extractedwith four 200 ml. portions of ethyl ether. These ether extracts werecombined and washed with water to remove some of the N,N-dimethylformamide. The ether layer was then extracted with a mixture of500 ml. of water and 17 ml. of concentrated hydrochloric acid. Theacidic extract was made strongly alkaline by addition of percent aqueoussodium hydroxide solution, and the oily base which separated fromsolution was collected and dissolved in ethyl ether. The ether solutionwas dried over anhydrous calcium sulfate and treated with decolorizingcharcoal. The mixture was filtered to remove the drying agent and thecharcoal, and the filtrate, which was almost colorless, was distilledunder reduced pressure to remove the ethyl ether. There was obtained asa residue a pale orange oil which weighed 39 g.', this product was 5,7-dichloro-4[2(1-piperidyl)ethoxy]indane, having the structural formula(when.

CHz-CHg B. The above base was converted to the hydrochloride bydissolving it in 200 ml. of isopropyl alcohol, and adding 5 N alcoholichydrogen chloride solution thereto until the mixture was acidic to Congored paper. The white crystalline solid which separated from solution wascollected on a filter. This product, which weighed 34 g. and melted at216-217" (3., was 5,7-dichloro-4-[2 (1-piperidyl) ethoxylindanehydrochloride. Analysis.Calcd. for c H Cl NQHcl: C, 54.79; H, 6.32; Cl,30.33. Found: C, 55.05; H, 6.53; Cl, 30.05.

C. Interaction of 5,7-dichloro-4-[2-( l-piperidy1)ethoxy] indane withone equivalent of ethyl iodide yields 5,7-di- 24chloro-4-[2-(l-piperidyl)ethoxylindane ethiodide, having the structuralformula OCIIICIIQAN CH1 Cut 1 CH:-CH -01 CH2 1 EXAMPLE24 This basereacts with one molecular equivalent of methyl iodide to yield4-[2-(1-piperidyl)ethoxy]indane methiodide, having the structuralformula /CH3 CH2-CH3 4- [3-(1-Piperidyl)Propoxyflndane Following theprocedure described in part A of Example 23, but substituting 26.8 g. of4-indanol for the 5,7-dichloro-4-indanol and substituting 32.4 g. of3-(1- piperidyl)propyl chloride for the 2-(l-piperidyl)ethyl chloride,there is obtained as the product 4-[3-(l-piperidyl)propoxy]indane,having the structural formula This base reacts with one equivalent ofmethyl iodide to yield 4-[3-(l-piperidyl)propoxy]indane methiodide,having the structural formula EXAMPLE 26 4- [2-(l-Hexamethyleniminyl)Ethoxyflndane Following the procedure described in part A of Example 23,but substituting 26.8 g. of 4-indanol for the 5,7-dichloro4-indanol andsubstituting 32.4 g. of 2-(1- 25 V hexamethylenirninynethyl chloride forthe Z-(I-piperidyl)ethyl chloride, there is obtained as the reactionprod net 4- [2-( l-hexamethylenirninyl)ethoxy1indane, having thestructural formula CHi-CHQ CH OCH2CH2N i 7 CH2 10 CH -CH; C n

This base reacts with one equivalent of methyl iodide to yield4-[2-(1-hcxamethyleniminyl)ethoxy]indane methiodide, having thestructural formula This base reacts with one equivalent of methyl iodideto yield 5-[2-( l-piperidyhethoxyjindane methiodide, having thestructural formula CH, CH2 0H2 moment-n CH2 0 {Y 1 our-oh,

EXAMPLE 28 5 [2-( 1 -H examethyleniminyl )Eth oxy I ndane 30 Followingthe procedure described in part A of Example 23, but substituting 26.8g. of S-indanol for the 5,7-dichloro-4-indanol and substituting 32.8 g.of 2-(1- hexamethyleniminyD-ethyl chloride for the 2-(1-piperidyDethylchloride, there is obtained 5-[2-( l-hexamethyleniminyl)ethoxy]indane,having the structural formula 011743112 CH2\ CH2 -oomc1nN I CH2 on,

onrcn, CH3

This base reacts with one equivalent of methyl iodide toyieldS-[2-(1-hexamethyleniminyl)ethoxy]indane methiodide, having thestructural formula CHg-CH: CHI 1 O-CH:CH:-N 1 CH1 CHz-CHz CH;

EXAMPLE 29 5- [3-(1-Piperz'dyl PropoxyJInddne Following the proceduredescribed in part A of Example 23, but substituting 26.8 g. of S-indanolfor the 5,7-dichloro-4-indanol and substituting 32.8 g. of 3-(1-piperidyDpropyl chloride for the 2-(1-piperidyl)ethyl chloride, there isobtained 5-[3-(l-piperidyl)propoxy]indane, having the structural formulaCHa CH2 CHQ O-CHgCH:CHgN /CH2 0 1 onronr This base reacts with oneequivalent of methyl iodide to yield 5-[3-(l-piperidyUpropoxy]indanemethiodide, having the structural formula CH3 CHz-CHK o-oH2crnom-1 v 0H,I om-orn EXAMPLE 30 5-{2-(I-Heptamethyleniminyl)EthoxyHndane When 35.7g. of 2-(1- eptamethyleniminyhethyl chloride is substituted for the 2-(l-hexamethyleniminyUethyl chloride in the procedure of Example 28, thereis obtained 5-{2-(l-heptamethyleniminyl)ethoxyJindane, having thestructural formula CH1CH3CH:

CHPCH2C 2 O-GHgCHrN CH3 1 This base reacts with hydrogen chloride toyield S-[Z-(lheptamethyleniminyl)ethoxylindane hydrochloride. The basereacts with one equivalent of methyl bromide to yield 5-[2-(l-heptamethyleniminyl)ethoxyJindane methobromide, having the structuralformula 0H, CH: CHr-CHg-CHK OCHrCH N 0111 om-cm-om EXAMPLE 31 5,7-Dichlor0-4- [3- (4 -M orpholinyl Propoxy] Indane A. Proceeding in accordancewith the manipulative procedure described above in part A of Example 23,the following we cuts were employed: 20.3 g. of 5,7-dichloro-4-indanol;ml. of N,N-dimethylformamide which had been dried over calcium hydride;4.8 g. of a 50 percent (by Weight) suspension of sodium hydride inmineral oil; and 17 g. of 3-(4-morpholinyl)propyl chloride. The reactionproduct thus obtained, which was 7 5,7 dichloro 4 [3 (4morpholinyl)propyl]indane, having the structural formula O -CHZCIDCHr-N/O our-on2 was isolated as an orange-yellow oil which weighed 12.5 g.

B. The above base was dissolved in 50 ml. of isopropyl alcohol, and tothis solution there was added alcoholic hydrogen chloride solution untilthe mixture was acidic to Congo Red paper. The finely divided whitesolid which separated from solution was collected on a filter. Thisproduct, which weighed 9.3 g. and melted at 160-174 C., wasrecrystallized from isopropyl alcohol. thus obtained 5 g. of5,7-dichloro-4-[3-(4-morpholinyl)- propoxylindane hydrochloride as 12.white crystalline solid.

C. Interaction of 5,7-dichloro-4-[3-(4-morpholinyl)- propoxylindane withone equivalent of n-propyl iodide yields 5,7 dichloro 4 [3 (4morpholinyl)propoxylindane n-propiodide, having the structural formula 1cutout EXAMPLE 32 4-[2-(4-M0rph0linyl) Ethxy1lndane Proceeding in themanner described in part A of Example 23, but substituting 13.4 g. of4-indanol for the 5,7dichloro-4-indanol and substituting 15.5 g. of2-(4- morpholinyl)ethyl chloride for the 2-(1-piperidyl)ethyl chloride,the product obtained is 4-[2-(4-morpholinyl)- ethoxy]indane, having thestructural formula This base reacts with one equivalent of methyl iodideto yield 4 [2 (4 morpholinyl)ethoxy]indane methiodide, having thestructural formula 5-[2-(4-M0rpholinyl)Ethoxy]Indane Proceeding in themanner described above in part A of Example 23, but substituting 13.4 g.of S-indanol for the 5,7-dichloro-4-indanol and substituting 15.5 g. of2-(4-morpholinyl)-ethyl chloride for the 2-(1-piperidy1)- There wasethyl chloride, there is obtained 5-[2-(4-morpholinyl)- ethoxy]indane,having the structural formula CH2 1 /crncrn \V -o-cmom N out i om oniThis base reacts with one equivalent of methyl iodide to yield 5 [2 (4morpholinyl)ethoxy]indane methiodide, having the structural formula Cm/cnl-on= O CHsCHZ N 0 on 1\ 1 I Gin-on,

EXAMPLE 34 5,7-Dichl r0-4- [Z-(J-Pyrrolidyl)Ethoxy Indane was obtainedas a colorless oil which weighed 33 g.

B. The above base was dissolved in 200 ml. of isopropyl alcohol, and thesolution was then acidified by addition of a solution of hydrogenchloride in ethyl ether. After the reaction mixture had stood for fourhours at room temperature, the white crystalline solid which hadseparated from solution was collected on a filter. This product, whichweighed 18.5 g. and melted at 178-179 C., was5,7-dichloro-4[2-(1-pyrrolidyl)ethoxy]indane hydrochloride.Analysis.-Calcd. for C H Cl NOHCl: C, 53.51; H, 5.99; Cl, 31.59. Found:C, 53.58; H, 6.12; Cl, 31.40. The base reacts with hydriodic acid toyield 5,7-dichloro-4-[2-( l-pyrrolidyl ethoxyl indane hydrioditle.

C. Interaction of 5,7-dichloro-4-[2-(1-pyrrolidyl)ethoxy]indane with oneequivalent of n-arnyl iodide yields5,7-dichloro-4-[2-(l-pyrrolidyl)ethoxy]indane n-amyl iodide, having thestructural formula EXAMPLE 4-[2-(I-PyrroIidyl)Et/z0xy}Indane Proceedingin the manner described in part A of Example 1, but substituting 26.8 g.of 4-indanol for the S-indanol and substituting 27 g. of2-(l-pyrrolidyl)ethyl chloride for the 3-diethylaminopropyl chloride,the prod uct obtained is 4-[2-(1-pyrrolidyl)ethoxy]indane, having thestructural formula GHQ-CH1 o-crncm-N cutout This base reacts withhydrogen chloride to yield the 4-[2-(l-pyrrolidyl)ethoxy1indanehydrochloride. The base reacts with one equivalent of lauryl bromide toyield 4-[2-(1-pyrrolidyl)ethoxy]indane lauryl bromide, having thestructural formula rton-cm CH2H -CH1CH9- CH: Bl CH2CH] .4

EXAMPLE 36 Proceeding in accordance with the manipulative pro ceduredescribed above in part A of Example 23, but using the fiollowingreagents: 26.8 g. of S-indanol; 250 ml. of anhydrousN,N-dimethylformamide; 9.6 g. of a 50 percent (by weight) suspension ofsodium hydride in mineral oil; and 27 g. of 2-(pyrrolidyl)ethylchloride, the reaction product obtained is5-[2-(1-pyrrolidyl)ethoxy]indane, having the structural formula CH: ou-cu. OCHzCH;-N CHr-CH;

This base reacts with one equivalent of methyl iodide to yield5-[2-(l-pyrrolidyl)ethoxylindane, having the structural formula5,7-Dz'chIor0-4-(2-Diisopropylaminoethoxy )Indane A. Following themanipulative procedure of part A of Example 23, the following reagentswere employed: 40.6 g. of 5,7-dichloro-4-indanol; 250 ml. of anhydrousN,N-dimethylforrnamide; 9.6 g. of a 50 percent (by weight) suspension ofsodium hydride in minenal oil, and 33 g. of 2-diisopropylaminoethylchloride. The reaction product was isolated as an orange oil whichweighed 58 g. This oil was distilled under reduced pressure. Thefraction distilling at 159163 C. was a colorless oil, n =l.5263, whichweighed 47.1 g.; this product 30 was 5,7-dichloro 4(Z-diisopropylaminoethoxy)indane, having the structural formula CH CEH,

CH(CH )2 EXAMPLE 38 7 -Brom 0-4- (Z-Dieth ylaminoethoxy Indane cumin A.Following the manipulative procedure of part A of Example 23, thefollowing reagents were employed: 15 g. of 7-bromo-4-indanol; ml. ofanhydrous N,N-dimethylformamide; 3.4 g. of a 50 percent (by Weight)suspension of sodium hydride in mineral oil; and 9.5 g. ofZ-diethylaminoethyl chloride. The reaction product, which was 7-bromo 4(2-diethylarninoethoxy)indane, having the structural formula wasisolated as a pale yellow oil weighing 19.8 g.

B. The above base was dissolved in 70 ml. of isopropyl alcohol, and thesolution was acidified with 12 m1. of 5.9 N alcoholic hydrogen chloridesolution. The white solid which separated from the solution wascollected on a filter. There was thus obtained 16 g. of 7-bromo-4-(2-diethylaminoethoxyfindane which melted at -176 C. Analyris.-Calcd. for CH BrNOHCl: C, 51.66; H, 6.65; Br, 22.9; Cl, 10.17. Found: C, 51.62; H,6.62; Br, 22.7; CI, 10.22.

C. Interaction of 7-bromo-4-(Z-diethylaminoethoxy)- indane with oneequivalent of diethyl sulfate yields 7-brorno-4-(Z-diethylarninoethoxy)indane ethosulfate, having thestructural formula Cam O--CH:CH2N /orn i Cam CH1 I somiui 31 EXAMPLE 397-Fluor0-4-(Z-Diethylaminoethoxy )Indane Proceeding as in part A ofExample 38 with the exception of substituting 10.6 g. of7-iluoro-4-indanol for the 7-bromo-4-indanol, there is produced7-fluoro-4-(2-diethylaminoethoxy)indane, having the structural formulaO-CHzCHz-N CIT-2 a (1H5 CHI 50 0 11 EXAMPLE 40 4-(Z-Dimethylamino-l-Methylcthoxy)Indane Following the procedure describedin part A of Example 23, but substituting 26.8 g. of 4-indanol for the5,7-dichloro-4-indanol and substituting 24.2 g. of 2-dimethylaminopropylchloride for the 2-(l-piperidyl)ethyl chloride, the reaction productobtained is 4-(2-dimethylamino- 1-methylethoxy)indane, having thestructural formula This base reacts with hydrogen bromide to yield4-(2-dimethylamino-l-methylethoxy)indane hydrobromide. The U base reactswith one equivalent of methyl iodide to yield 4- (Z-dimethylamino- 1-rnethylethoxy) indane methiodide,

having the structural formula EXAMPLE 415-(Z-Dimethylamina-1-Methyleth0xy)Indane This base reacts with glutamicacid to yield 5-(2-dimethylamino-l-methylethoxy)indane glutamate. Thebase reacts with one equivalent of methyl iodide to yieldS-(Z-dimethylamino-l-methylethoxy)lndane methiodide, having thestructural formula Oil EXAMPLE 425,7-Dichl0r0-4-(2-Dimethylaminopropoxy)Indane and 5,-7-Dz'chl0r0-4-(Z-Dimethylamino-I -Metlrylethoxy)Indane A. Following themanipulative procedure of part A of Example 16, the following reagentswere employed; 20 g. of 5,7-dichloro-4-indanol; ml. of anhydrousN,N-dimethylformamide; 4.8 g. of a 50 percent (by weight) suspension ofsodium hydride in mineral oil; and 10.5 g. of a mixture ofZ-dimethylarninopropyl chloride and 2-dimethylamino-Z-methylethylchloride obtained by treating Z-dimethylaminopropyl chloridehydrochloride with sodium hydroxide solution. The reaction product wasisolated as a colorless oil weighing 13.5 g. which consisted of amixture of 5,7-dichloro-4-(Z-dimethylaminopropoxy) indane, having thestructural formula Cl and5,7-dichloro-4-(Z-dimethylamino-l-methylethoxy)indane, having thestructural formula This mixture was distilled under reduced pressure.The three major fractions were as follows: 1.9 g., distilling at 124137C., n =1.5384; 1.8 g., distilling at 137-142 C., n :l.5385; and 7.5 g.,distilling at 142-146" C., n =1.5394.

Analysis.--Calcd. for C H Cl NOz N, 4.86. Found: N, Fraction 1:4.82,Fraction 2:4.80, Fraction 3:4.77.

EXAMPLE 43 5,7-Dichl0ro-4-(3-Dimethylaminopropoxy)Indane A. Followingthe manipulative procedure of part A of Example 23, the followingreagents were employed: 20.3 g. of 5,7-dichloro-4-indanol; ml. ofanhydrous N,N- dimet hylformamide; 4.8 g. of a 50 percent (by weight)suspension of sodium hydride in mineral oil; and 20 g. of3-dimethylaminopropy1 chloride. The reaction product, which was5,7-dichloro-4-(3-dimethylaminopropoxy)indane, was isolated as a yellowoil which Weighed 18 g., representing a considerably better yield ofthis base by this procedure than by the method of part A of Example 22.

B. The above base Was dissolved in 100 ml. of isopropyl alcohol and thesolution was made acidic to Congo red paper by addition of an ethylether solution of hydrogen chloride. The white solid which separatedimmediately from solution was collected on a filter. There was thusobtained 18 g. of 5,7 dichloro-4-(3-dimethylaminopropoxy)indanehydrochloride which melted at 209-210 33 C. Analysis-Calcd. for C l-l ClNQHClz Cl, 32.76. Found: Cl, 32.90.

EXAMPLE 44 7-Chl0r0-6-Methyl-4-[2-(2,6-DimethyI-1-Piperidyl)Ethoxy]lndane A. A commercial grade of 6-methyl-4-indanol (Carbide andCarbon, M.P. 82-84 C., was recrystallized with charcoaling frompetroleum ether to obtain flufr'y white needles. 25 g. of this productwas dissolved in 35 ml. of glacial acetic acid and a small crystal ofiodine was added as a chlorination catalyst. The resulting solution wasstirred, and 23 g. of sulfuryl chloride was added dropwise while keepingthe temperature of the reaction mixture below 45 C. by external coolingwhen necessary. After all of the sulfuryl chloride had been added, thereaction mixture was stirred for a few minutes and then a solidseparated from solution. This solid was collected on a filter, waswashed with acetic acid, and then was dried. This product, which weighed17.5 g. was recrystallized twice from petroleum ether. There was thusobtained 11.5 g. of fluffy white needles which melted at 120-122" (1.;this product was 7-chloro-6-methyl-4-indanol, having the structuralformula CH 5 C 2 Analysis.-Calcd. for C H ClO: C, 65.75; H, 6.07; Cl,19.42. Found: C, 66.07; H, 6.39; Cl, 19.11.

B. Proceeding as described in part A of Example 23, but substituting36.4 g. of 7-chloro-6-methyl-4-indanol for the 5,7-dichloro-4-indanoland substituting 35.7 g. of 2-(2,6-dimethyl-1-piperidyl)ethyl chloridefor the 2-(1- piperidyl)-ethyl chloride, there is obtained 7-chloro-6-methyl-4-[2-(2,6 dimethyl 1 piperidyl)ethoxy]indane, having thestructural formula CH2 oruoHa-cm on ons-org C42 Br EXAMPLE 455,7-Dichlor0-6-Methyl-4-[2-(3-MethyZ-I -Pyrr0lidyl Ethoxy] I ndane A. 30g. of 6-methyl-4-indanol was slurried in 50 ml. of glacial acetic acidand a small crystal of iodine was added as a chlorination catalyst. Theslurry was stirred and 58 g. of sulfuryl chloride was added dropwise atsuch rate that the temperature of the reaction mixture remained 34 below55 C. without application of external cooling. After this addition wascompleted, the reaction mixture was stirred for one hour longer, duringwhich period a solid separated from solution. This solid was collectedon a filter, and was washed with acetic acid and then dried. There wasthus obtained 35 g". of white solid; this was recrystallized from 300ml. of petroleum ether. There was thus obtained 28 g. of silky whiteneedles which melted at 99102 C. This product was 5,7-dichloro-6-methyl-4-indanol, having the structural formula OH CH: I

Anaiysis.--Calcd. for c d-1 C1 0: C, 55.31; H, 4.64; Cl, 32.66. Found:C, 55.16; H, 4.70; Cl, 32.19.

B. Following the procedure of part A of Example 1, but substituting 40.6g. of 5,7-dichIoro-6-methyl-4-indanol for the S-indanol and substituting29.6 g. of 2-(3- methyl-l pyrrolidynethyl chloride for the3-diethylaminoethyl chloride, there is obtained 5,7-dichloro-6-methyl-4-[2-(3 methyl l -pyrrolidyl)ethoxy]indane, having the structural formulaCHr -CHCHg O-CH:OH2N our-on.

CH; CH,

This base reacts with methanesulfonic acid to yield 5,7-dichloro-6amethyl-4-[2-(B-methyl-l pyrrolidyl)ethoxy}- indanemethanesulfonate. The base reacts with u-propyl iodide to yield5,7-dichloro-6-methyl-4-[2-(3-methyl-lpyrrolidyl)ethoxy]indanepropiodide, having the structural formula CHzCHgCHs OHz-CH(CH&)o-mmom-rq Q 01 I our- H, C I

OH; OH

EXAMPLE 46 5 7-Dichi0r0-4- [1-Methyl-5( l-Pr'peridyl) Pentoxy] IndaneProceeding in the manner described in part A of Example 23, butsubstituting 37.8 g. of I-methyl-S-(l-piperidyl)pentyl chloride for the3-(1-piperidyl) propyl chloride, there is obtained5,7-dichloro-4-[l-methyl-S-(lpiperidyl)pentoxy]indane, having thestructural formula This base reacts with Z-naphthoic acid to yield5,7-dichloro-4-[l-methyl 5 (1 piperidyDpentoxylindane 2- naphthoate. Thebase reacts with dimethyl sulfate to 35 yield5,7-dichloro-4-[l-methyl-S-(l piperidyl)pentoxy]- indane methosulfate,having the structural formula 6-Chloro-5-(Z-Diethylaminoethoxy)Indane A.10 g. of sodium hydride was added to 400 ml. of isopropyl alcohol in aone liter three-neck flask fitted with a refiux condenser, drying tube,stirrer, and dropping funnel. The resulting solution was heated toreflux and stirred, and 50 g. of Z-diethyIaminoethyl chloride was addedto the refluxing solution dropwise over a period of fifteen minutes.After this addition was completed, the reaction mixture was refluxed forone hour more, and then the excess isopropyl alcohol was distilled off.The distillation residue was diluted with water and extracted with ethylether. The ether layer, was separated and extracted with a mixture of960 ml. of water and 75 ml. of concentrated hydrochloric acid. The acidaqueous extract was made alkaline by addition of excess 35 percentaqueous sodium hydroxide solution. The oily base which separated wasdissolved in ether, and the ether solution was dried over anhydrouscalcium sulfate. After removal of the drying agent, the ether wasremoved from the solution by distillation, and the residual oil wasdistilled under reduced pressure. The fraction distilling at 145-180 C.(0.05 mm.) was a colorless oil, n 1.5277, which weighed 40.7 g. Thisproduct was 6- chloro-S-(Z-diethylaminoethoxy)indane, having thestructural formula .4. i CH B. 40 g. of6-chloro-5-(2-diethylarninoethoxy)indane, 125 ml. of isopropyl alcohol,and 41.3 ml. of 4.16 N ethanolic hydrogen chloride solution were mixedand the mixture was then cooled. Ethyl ether was added to the cooledsolution, just short of turbidity. The solid which separated fromsolution on standing was collected on a filter. This product, whichweighed 23.3 g. was recrystallized from isopropyl alcohol, usingdecolorizing charcoal, to yield 10 g. of6-chloro-5-(Z-diethylaminoethoxy) indane hydrochloride which melted at150-152 C.

Analysis.Calcd. for C H CI NO: Cl (total, 23.30; Cl (ionic), 11.65.Found: Cl (total), 23.03; Cl (ionic), 11.69.

36 C. 6chloro-5-(2 diethylarninoethoxy)indane reacts with one equivalentof p-ethoxybenzyl chloride to yield 6-chloro-5(2diethylaminoethoxy)indane p-ethoxybenzyl chloride, having the structuralformula.

CH2 CZH5 O-CHzCHq-N 01 can EXAMPLE 48 5, 7-Dich I0r0-4- [2-(4-Thi0m0rph0linyl )EthoxyJIndane ethoxy]indane methiodide, having thestructural formula on, om\ 0o1noHI I 1 orb-cm I claim: 1.5,7-Bis(dimethylaminomethyl)-4-indanol. 2.4,6-Bis(dimethylaminomethyl)-5-indanol.

References Cited in the file of this patent UNITED STATES PATENTS SamJan. 21, 1958 Huebner Jan. 31, 1961 OTHER REFERENCES Fieser et al.: J.Am. Chem. Soc., volume 58, pages 20502054 (1936).

1. 5,7-BIS(DIMETHYLAMINOMETHYL)-4-INDANOL. 2.4,6-BOS(DIMETHYLAMINOMETHYL)-5-INDANOL.